An alternate protein is taken up by other cells, in some cases killing them.

Most cancers result from a combination of mutations in genes that normally control a cell's growth. Some of these, called oncogenes, normally push a cell to divide; mutations in these tend to make them more active, pushing the cell to divide ever faster. Then there are tumor suppressors. Their normal role is to put a check on growth, and mutations in these genes tend to eliminate their function, easing off the brakes on a cell's division.

Now, scientists have discovered a well-known tumor suppressor gene doesn't only slow down the growth of the cells it's produced by. Instead, a previously undiscovered form of the protein gets shipped out of the cell and inserts itself into other cells, where it also shuts down growth. In the case of some tumor cells, this sudden shutdown appears to be sufficient to kill them.

The PTEN tumor suppressor gene has been studied for well over a decade. Many of the signaling pathways that help push a cell to divide involve proteins that chemically link a phosphorous to other proteins (these are called "kinases"). The product of the PTEN works by undoing this chemical modification, removing phosphates from proteins and some signaling molecules (technically, it's a "phosphatase"). In doing so, it blocks a variety of growth-stimulating signals. It plays such an essential role in shutting down growth that many cancers from many different cell types have been found to have mutations that wipe out PTEN activity.

Most of the years of study have focused on the biochemical activity of PTEN and its interactions with other genes implicated in cancer. Somehow, over that time, an odd feature of the PTEN gene itself was missed. Like most other genes, the PTEN gene produces an RNA transcript that is translated into a protein starting at a specific sequence of bases: AUG. After the AUG, there's a long stretch of bases without any stop codes; this stretch encodes the PTEN protein.

But someone (presumably one of the authors of this paper) also noticed something a bit odd: there were no stop signals for quite a distance in front of the AUG as well. And quite a distance in front of the AUG, they found a different signal, CTG, that cells very occasionally use to start a protein. All of this suggested there might be a second form of the PTEN protein, one that everyone had missed. The researchers confirmed that two different sized proteins were recognized by antibodies against PTEN, and they showed that the long version of the protein could be made from the PTEN gene in many species. So two forms of the protein exist, and both are probably important.

This long form was nearly half again as long as the regular PTEN protein, so the researchers started trying to figure out what it could be doing. The first thing they discovered was that it had a sequence of amino acids that would cause the protein to be shipped outside of the cell. OK, you might think (and I'm sure the researchers did), maybe there are some phosphates outside the cell that need to be removed, and this form of PTEN takes care of that. But the authors found that the long version also had a sequence that let it slip back into cells. This form of PTEN appeared to get shipped out of one cell and received by the cell's neighbors.

To confirm this, they hooked up the extra bit of sequence to a red fluorescent protein. When they did this, neighboring cells would start to glow red. When cells were exposed to a soluble version of the long form of PTEN, the cells picked that up as well. Once inside a cell, the protein did what it normally did, removing phosphates from key growth regulators.

It appears that PTEN not only regulates the growth of the cells it's made in; it can also shut down growth of neighboring cells. In normal cells, this could help populations coordinate their growth directly, making sure that groups of cells slow down in synchrony when an organ is done developing or speeding up growth to repair an injury.

But what happens if the cells are already growing out of control—when they've become cancerous? The authors checked that too. In culture, cancer cells did not like the combination of many mutations urging them to divide and a lot of PTEN telling them to slow down. In response to the confusion, they died. This also happened in living animals. When tumor cells are implanted under the skin of immunocompromised mice, they will grow into new tumors. When these same mice were given abdominal injections of the long form of PTEN, the tumors shrunk, in some cases vanishing entirely.

Before you get overly optimistic, lots of things can clear these sorts of tumors out of mice, so this doesn't mean we're looking at a cure for cancer. But it certainly suggests that the long form of PTEN may normally play a role in modulating the growth of tumors. And understanding how could certainly prove useful.

22 Reader Comments

Theoretically speaking, it could cause cancer cells to die, but couldn't it do the opposite as well? PTEN just regulates growth so couldn't it go in either direction? Also how do they target just the cancer cells? Also we probably need to know more about just why the cancel cell dies in the confusion. I don't really like the idea of proteins just floating around telling its neighbors to die. (oh there is a little comic strip in that one somewhere)

The floating around telling neighbors to die would be fine if it only acted on those who got "confused."

Wish my mom had something like this that worked. She's been successfully fighting Stage 3 ovarian cancer for about 5 years, which is about all anyone expects for life expectancy from such a diagnosis.

After a year's break from chemo in 2011 it came back. They haven't given up on her but now they've "paused" chemo while trying something else intended to do just what this article's about, stop growth of cancer cells.

This protein doesn't tell cells to die, it tells them to slow down their dividing rate.

The tumor cells die because the cell death mechanism recognizes a massive "DIVIDE NOW!!!" signal and a massive "SLOW DOWN!!!" signal shouldn't be happening at the same time so it commits suicide. There are a bunch of regulation pathways that act as dead-man switches, etc precisely to prevent cells from growing out of control, including some that are internal to the mitochondria and not part of our regular DNA at all.

Presumably it's all part of the evolution of multicellular animals as cells turned on their biofilm genes continuously, then took on mitochondria as symbiotes. Any organism that didn't evolve heavy regulation mechanisms would be vulnerable to a few cells deciding "screw this, we're going it alone".

Theoretically speaking, it could cause cancer cells to die, but couldn't it do the opposite as well? PTEN just regulates growth so couldn't it go in either direction? Also how do they target just the cancer cells?

PTEN is primarily known as a negative regulator of PI3K/Akt (high PTEN = low p-PI3K and vice versa). p-PI3K results in increased cell growth and activates metastasis via a variety of signaling pathways. So injecting PTEN into a tumor won't cause growth.

Usually cancer cells are more hardy to external stress, but there's the possibility that normal cells already have a higher level of PTEN. Due to the rapid proliferation of cancer cells, PTEN might be enough to destabilize them and cause cell death. Honestly, they only have a trypan blue assay there. I'd like to see a LDH measurement, or a Annexin V/propidium iodide stain on confocal or flow cytometry for a more robust confirmation of cell death.

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Also we probably need to know more about just why the cancel cell dies in the confusion. I don't really like the idea of proteins just floating around telling its neighbors to die. (oh there is a little comic strip in that one somewhere)

After reading the paper, PTEN appears to be naturally secreted (has a domain specific for secretion). Normally PTEN-Long isn't produced in high levels, but a little mutation caused higher levels to be secreted.

As for proteins floating around telling neighbors to die, does TNFa ring a bell? Secreted by T-cells, macrophages, neurons etc.

"Some of these, called oncogenes, normally push a cell to divide; mutations in these tend to make them more active, pushing the cell to divide ever faster. Then there are tumor suppressors. Their normal role is to put a check on growth, and mutations in these genes tend to eliminate their function, easing off the brakes on a cell's division."

So, mutations in the "accelerator" cause the cancer to speed up, and mutations in the "brake"... also cause the cancer to speed up.

I don't really like the idea of proteins just floating around telling its neighbors to die.

Inducing the death of cells that aren't needed any more is vital, not only in development but also in the day-to-day maintenance of an organism's cellular structure. Look up apoptosis - the factors involved in killing cancer cells (TNF etc) are actually primarily used in managing cells on a far wider basis. If you don't take out the trash, it'll end up blocking your driveway.

"Some of these, called oncogenes, normally push a cell to divide; mutations in these tend to make them more active, pushing the cell to divide ever faster. Then there are tumor suppressors. Their normal role is to put a check on growth, and mutations in these genes tend to eliminate their function, easing off the brakes on a cell's division."

So, mutations in the "accelerator" cause the cancer to speed up, and mutations in the "brake"... also cause the cancer to speed up.

No wonder cancer is such a horror. Evolution, you bastard.

Yep. Once you realize that cancer is evolution on steroids and crack, you can see why trying to kill it is so hard.

Would be interesting to know how this affects mitochondria in normal cells. Wouldn't want to cure cancer and make us all Type II Diabetic or Cold Blooded if it kills them off. Also wouldn't want it to do the reverse and make us into rage zombies.

Just noting a minor technical detail here, but regarding the statement "And quite a distance in front of the AUG, they found a different signal, CTG...," AUG is an RNA sequence and CTG is a DNA sequence.

I think if we found a cure for cancer we wouldn't release it. Cancer research and treatment is just too big of a business to be undone. The scientists will be aghast at this statement and rightly so, as they are working for a cure. But their places of employment are not managed by scientists, but by corporate managers, and their job is to keep the business going. A cure would put them out of business, so it isn't in their best interest to release it. Look around you, for the last 20 years, the main focus hasn't been on humanity but greed and profit. We don't do anything if it doesn't make us money or keep it flowing.

I think if we found a cure for cancer we wouldn't release it. Cancer research and treatment is just too big of a business to be undone. The scientists will be aghast at this statement and rightly so, as they are working for a cure. But their places of employment are not managed by scientists, but by corporate managers, and their job is to keep the business going. A cure would put them out of business, so it isn't in their best interest to release it. Look around you, for the last 20 years, the main focus hasn't been on humanity but greed and profit. We don't do anything if it doesn't make us money or keep it flowing.

I expect that a cure for cancer would consist of a treatment process, emphasis on process, instead of something unrealistic like taking a single dose of a drug or taking a pill for 30 days. And so process implies inpatient treatment, over a period of time, and we all know that time spent in a hospital isn't exactly cheap. So the money lost on cancer drugs would likely be partially replaced by the money spent on the treatment itself, the associated machinery if any, training for the doctors and nurses, the materials administered to the patient, etc.

Furthermore, it would be ridiculously expensive, the way that stem cell treatment is expensive today. And so that would limit its use to the top 10%, or 5%, or 1%, whatever. So not only would the pharma company make assloads of cash on the treatment itself, it would still be selling traditional cancer drugs to the other 90% of the population that is too poor for top of the line doctors and treatments.

And last, there would be tons of prize money in it for the pharm company, and it would have exclusive rights via patent to the CURE FOR CANCER! Hah this would be an absolute *coup* for whichever company developed it. I don't think we have to worry about pharm companies holding back a potential cure; there's just too much money to be *made*, not lost.

Now, that's not to say pharm companies aren't shiesty-ass motherfuckers that need to be kept in check, and aren't at the moment.

I think if we found a cure for cancer we wouldn't release it. Cancer research and treatment is just too big of a business to be undone. The scientists will be aghast at this statement and rightly so, as they are working for a cure. But their places of employment are not managed by scientists, but by corporate managers, and their job is to keep the business going. A cure would put them out of business, so it isn't in their best interest to release it. Look around you, for the last 20 years, the main focus hasn't been on humanity but greed and profit. We don't do anything if it doesn't make us money or keep it flowing.

I think if we found a cure for cancer we wouldn't release it. Cancer research and treatment is just too big of a business to be undone. The scientists will be aghast at this statement and rightly so, as they are working for a cure. But their places of employment are not managed by scientists, but by corporate managers, and their job is to keep the business going. A cure would put them out of business, so it isn't in their best interest to release it. Look around you, for the last 20 years, the main focus hasn't been on humanity but greed and profit. We don't do anything if it doesn't make us money or keep it flowing.

Are you kidding? A cure for cancer would suddenly free up a humongous swathe of a pharma company's R&D staff and funding to work on things that people will want to buy instead of have to buy because of disease. Things like an effective hair loss treatment or dramatically improve sexual satisfaction or self-confidence.

You know, the kind of things that people will buy and continue to buy because it increases personal gratification instead of in a desperate attempt to keep a ravening evolutionary monster in check.

That market must be there because I keep getting spam about Viagra for sale.

I think if we found a cure for cancer we wouldn't release it. Cancer research and treatment is just too big of a business to be undone. The scientists will be aghast at this statement and rightly so, as they are working for a cure. But their places of employment are not managed by scientists, but by corporate managers, and their job is to keep the business going. A cure would put them out of business, so it isn't in their best interest to release it. Look around you, for the last 20 years, the main focus hasn't been on humanity but greed and profit. We don't do anything if it doesn't make us money or keep it flowing.